DESCRIPTION (Verbatim from Applicant's abstract): Epidemiological data show that obesity is associated with an increased risk of hypertension. The pathophysiological processes underlying this frequent association are poorly understood. Orexin A and B are two recently isolated peptides expressed in a population of neurons in the rat lateral hypothalamus. The peptide upon intraventricular injection increases food consumption in rodents. Orexin A-immunoreactive (ORXA-LI) fibers project to areas of the rat brainstem including the rostral ventrolateral medulla (RVLM), the nucleus of the solitary tract, nucleus ambiguous and the dorsal motor nucleus of the vagus that provide direct control of autonomic neurons. The presence of ORXA-LI fibers in the RVLM raises the possibility that the peptide may also be involved in the medullary regulation of the sympathetic outflow to the spinal cord. Our initial study shows that orexin A and B injected intracisternally or microinjected into the RVLM increased blood pressure and heart rate in anesthetized rats. In this renewal application, a multidisciplinary approach will be employed to test the hypothesis that orexin A and B may interact with RVLM neurons and enhance sympathetic outflow in the rat. First the distribution of orexin-like immunoreactivity in the rat brain will be characterized. Second the effects of orexin A or B by microinjection to the RVLM area on blood pressure and heart rate in awake rats will be assessed. Third, whole cell patch recordings will be made from RVLM neurons of brainstem-spinal cord preparations or coronal brainstem slices. Recorded neurons will be labeled with Lucifer yellow and later processed for PNMT-immunoreactivity for identification purposes. The effects of orexin A or B on the electrical activity of RVLM neurons will be studied with respect to ionic and signal transduction mechanism. Overweight and hypertension are two major health problems in the United States. Identification of the putative transmitters and the circuitry linking the hypothalamus to the autonomic nervous system will be a significant improvement in our understanding of the regulatory mechanisms underlying these disorders.